Phenoxyphenyl propyl amines



latented Oct. 1948* UNITED STATES PATENT OFFICE PHENOXYPHEI IfEfIZOYYL ANHNES Robert Biedermann,

to J. R. Geigy -A.G,, firm No Drawing.

4 Claims. 1

It has been found that therapeutically valuable compounds which are araliphati'c amines of the general formula wherein X means either an unsubstituted diphenyl ether radical or diphenyl ether radical substituted for instance by alkyl, alkoxy or hydroxy groups, Ri'means hydrogen or an alkyl radical, and R2 means hydrogen or an alkyl radical,

will be obtained by converting ketones of the general formula X-oH2-'on'c=o 53 wherein R is hydrogen or methoxy, R1 is hydrogen, methyl or methoxy, and-Rzis methyl or ethyl.

The conversion of the above defined ketones into the corresponding primary or secondary amines can be eiiected according to the most various known methods. Secondary amines may preferably be produced by-treating the ketones with reducing agents, like amalgamated aluminium or catalytically activated hydrogen, in the presence of the amines to be introduced. When working according to the catalytic hydrogenation method in the presence of ammonia primary amines may also be made. The Leuckarts method can be used for the production of primary and secondary amines. According to this method the above defined ketones are condensed with formamide or with the formyl compounds of monoalkylamines and the resulting iormyl compounds of the amines saponified to give the free amines. Furthermore, the ketones can be reduced to the secondary alcohols, the latter beii'i'g then 'esterified by means of a hydroh'alog'enic Basel, Switzerland, assignor Basel, Switzerland, a Swiss Application May 7, 1946, Serial No.

In Switzerland May 8', 1945 (C1. Zin -570.8)

and the resulting esters interacted with am- Primary amines of acid monia or monoalkylamin'es. the above defined formula may also be obtained from the oxim'e's or hydrazones of the keton'es by reducing the latter. Finally there may be mentioned that unsaturated ketones can'be converted into the corresponding amines according to any one of the above described methods of hydrogenating amination, while simultaneously saturating the double bond.

Secondary amines may also be obtained by alkylation of the corresponding primary amines, as has already been mentioned above. For such a substitution of the amino group the known methods may be used; the most convenient method is that consisting in the interaction with hydrohalo'genic esters or with sulfuric esters of alcohols or the interaction with aldehydes or ketones with reduction and the like. If desired, groups present in the diphenyl ether radical can also be transformed after the amination. As examples may be mentioned: the conversion of the nitro group over the amino group into the hydroxy group, the splitting of alkoxy groups, saponificat-ion of 'acyloxy groupings to hydroxy groups and so on. If "halogen atoms linked to an aromatic radical are present in the start- 20 parts of l-i'4'-(4" methoXyphenoXy) phenyll -pentanone-('3) (made by condensation of 4-(4' rnethoxyphenoxy) -ben-zaldehyde with methyl ethyl 'ketone and by subsequent hydro'genation offt'he double 'bond') and 10 parts of an aqueous 41% methylainine solution are dissolved in parts of 94% alcohol and treated at SO-60 "C. with '7 parts of amalgamated .aluminium. After completion of the reaction the resulting aluminium hydroxide is filtered oif, the filtrate being then evaporated. The base is dissolved in dilute hydrochloric acid, the non-basic ingredients present therein are removed by extraction of thesolutidn with ether, the base again made free by means of a sodium hydroxide solution and again extracted with ether. The resulting'ethereal solution is dried with anhydrous 'sodium sulfate, the "solvent expelled and the free base distilled in high-'vacuo. The 1'- 4"'-("4"'*- 3 methoxyphenoxy) -phenyll 3 N-methylaminopentane boils at 152 C. under a pressure of 0.03 mm.

The same final product is also obtained by In the same manner as that described in the above example there may be produced the 1-[4'- (i"-ethoxyphenoxy) phenyl] 2 methyl 3- aminopentane.

aminatin hydrogenation of 4-(4-methoxy- 5 Example 4 phenoxy)-styrylethylketone in the presence of platinum oxide. In an analogous manner the 9 p ts of 1- 4' "-a n ph 0 y) -pl methoxy group can be split by ea s f hy- 2-methyl-3-N-ethylam1nopentane are dissolved drobromic acid. in dilute sulfuric acid and diazotized with the Example 2 10 calculated quantity of sodium nitrite. Then the i 0 reaction mass is immediatel heated on the 20 parts of 1- [4'- (4"-methoxyphenoxy) water-bath until any development of nitrogen has phenyl]-2-methylpentanone-(3) (prepared from ceased. The resulting 1-[4=-(4"-hydroxyphe- 4-(4'-methoxyphenoxy) -benzy1 chloride and dinoXy)-phenyl]-2-methyl-3 N ethylaminopenethyl ketone in toluene in the presence of sodium tane is recovered from this solution by precipiamide) together with 9 parts of an aqueous 66% tation by means of ammonia, then filtration and ethylamine solution are dissolved in 150 parts by 'finally washing the product. The melting of 94% alcohol and treated at 50-60 C. with 7 point of the pure hydrochloride amounts to parts of amalgamated aluminium. Working up 170 C. is then effected in the manner described in EY- 90 When Working in the manner described in ample 1. Instead of amalgamated aluminium, any one of the above examples, the following comthere may also be used platinum oxide for hypounds may be made.

Table M. P. of Substance B P gi g flee the hydrochloride 1-[4-(4-methoxyphenoxy)-phenyl]-3-N-etl1ylaminopentane P. 0.00 162 C 1-[4-(4-hydroxyphenoxy)-phenyll-Zi-N-ethylaminopentanc g 170 0. 1-[4-(4-methoxyphenoxy)-phenyl]-2-methyl-3-N-mothylamino P. 0, 172 C l-(3-phenoxy-4-methoxyphenyl)-2-methyl-3-N-methylaminopentane B. P. 0.00 172 C 1-(3-phenoxy-4-meth0xypheny1)-2-methyl 3-N ethylaminopentane B. P. .1 178 C l-[3-(4"-methyl-phenoxy)A-methoxyphenyll-Z-methyl-ii-N-methylaminopentane B. P. 0.00 172 C 1-[3-(4-methylphenoxy)-4-methoxyphenyl]-2-methyl-3-N-ethylaminopentane. B. P. 0.0 187 C 1-l3-(2-methbxyphenoxy)-4-metl1oxyphen;, l]-2-1nethyl-3-N-methylaniinopentane B. I. 0.05 171 C l-[3-(2-methoxypl1enoxy)-4'-metl1oxyphenyl]-2-methyI-S-N-ethylaminopentane B. P. 0,4 182 C 1-(4'-phen0xy henyl)-2methyl-3-l T-methylaminopentane B. P. 0, 143" 0 l-(4-phenoxypheny1)-2-metl1yl-3-N-ethylamil10pcntane B. P. 147 C 1-[4-(4-hydroxyphenoxy)-pl1enyl]-2-methyl-3-N-methylaminopentane B. P. M 195 C. l-[3-methyl-4-(4-methoxyphenoxy)-phenyl]-2-methyl-3-N-methylarninopentane B. P. 0,01173" C l-[3(2-Inethylphenoxy )--methoxypheny1]-2-methyl-3-N-methylaminopentane B. P. 0 171 C drogenation purposes. The obtained 1-[4'-(4- methoxyphenoxy)-phenyl] 2 methyl 3 N- ethylaminopentane distills at 163 C. under 0.1 mm. pressure.

The 1-[4-(4-ethoXy-phenoxy)-phenyl] 2- methyl-3-Nethylaminopentane can be obtained in an analogous manner.

Example 3 parts of l-[e-(4=-methoxyphenoxy) phenyll-2-methyl-pentanone-(3) are heated for 8 hours to 165-17 0 C. with 24 parts of formamide. After cooling to 80 C. the formyl compound is treated with 100 parts of concentrated hydrochloric acid and the Whole subjected to hydrolysis by heating under reflux for 3 hours. Then it is allowed to cool, diluted with water and the base made free by means of concentrated caustic soda lye. Then it is extracted with ether, the ether distilled oil and the residue dissolved in dilute hydrochloric acid. This hydrochloric acid solution is treated with animal charcoal, filtered and the base again set free by means of caustic soda lye. It is extracted once more with ether, the ethereal solution dried over anhydrous Glaubers salt, the ether subsequently distilled off and the base fractionated. The resulting l- [4-(4"-methoxyphenoxy) -phenyll 2 methyl- 3-aminopentane distils at 164 C. under a pressure of 0.2 mm.

The same product is also obtained by reduction of the oXime of the l[ i'-(4"-methoXyphenoXy) phenyll-2-methylpentanone-(3) by means of sodium amalgam in glacial acetic acid.

The resulting primary amine can be alkylated with formaldehyde in the presence of a reducing agent, like amalgamated aluminium.

What I claim is: 1. An araliphatic amine of the formula wherein R represents a member selected from the group consisting of hydrogen and methoxy, R1 represents a member selected from the group consisting of hydrogen, methyl and methoxy and R2 represents a member selected from the group consisting of methyl and ethyl.

2. An araliphatic amine of the formula Ha C2H5 ROBERT BIEDERIWANN.

REFERENCES CITED The following references are of record in the file of this patent:

Kulz 2,407,167, Sept. 3, 1946 (published April 20, 1943, as A. P. C., S. N. 4:15,519 

